The present invention is concerned with new 5-arylalkyl-4-alkoxy-2(5H)-furanones, processes and intermediates for the preparation thereof and pharmaceutical compositions containing them.
The new 5-arylalkyl-4-alkoxy-2(5H)-furanones according to the present invention are compounds of the formula: ##STR2## wherein the oxygen atoms on C-5 and C-.alpha., relative to one another, are in the threo-position and wherein n is 0, 1 or 2, R.sup.o is a hydrogen atom or an alkyl radical containing up to 3 carbon atoms, R.sup.1 a straight-chained or branched alkyl radical containing up to 5 carbon atoms, R.sup.2 is a hydrogen atom, an alkyl radical containing up to 3 carbon atoms or the radical ##STR3## wherein R.sup.5 is an alkyl radical containing up to 5 carbon atoms or an ethoxyethyl or methoxyethyl radical and R.sup.6 is a hydrogen atom, an alkyl radical containing up to 5 carbon atoms or a methoxymethyl radical, R.sup.3 and R.sup.4, independently of one another, are hydrogen, fluorine, chlorine or bromine atoms, alkyl radicals containing up to 3 carbon atoms, perfluoroalkyl radicals containing up to 3 carbon atoms, a difluoromethoxy radical or a nitro group, with the exclusion of those compounds of formula (I), wherein R.sup.2 is H or CH.sub.3 when n=0 or 2, R.sup.o =H, R.sup.1 =CH.sub.3, R.sup.3 =H and R.sup.4 =H.
Furthermore, the present invention provides intermediates and processes for the preparation of the abovementioned compounds, as well as the use of these compounds as therapeutic active materials and also medicaments which contain the mentioned compounds and the compounds excluded from the scope of protection by the disclaimer.
Since the compounds of formula (I) with the asymmetric carbon atoms C-5 and C-.alpha. contain two chirality centres in their molecule, there are two diastereomeric pairs, namely, the two threo enantiomers: ##STR4##
The present invention is concerned exclusively with the two threo-enantiomers which can be present in the form of their racemate or of their two laevo or dextro-rotatory optical antipodes, as well as with processes which lead stereoselectively to the threo-enantiomers.
The compounds excluded by disclaimer from the product protection are known:
4-methoxy-5-phenylhydroxymethyl-2(5H)-furanone was described by A. Pelter et al., Tetrahedron Lett., 1979, p. 1627-1630; PA0 4-methoxy-5-[methoxy-(phenyl)-methyl]-2(5H)-furanone by A. Pelter et al., Tetrahedron Lett., 1982, p. 5229-5232; PA0 4-methoxy-5-(.alpha.-hydroxy-.gamma.-phenylpropyl)-2(5H)-furanone and 4-methoxy-5-(.alpha.-methoxy-.gamma.-phenylpropyl)-2(5H)-furanone were described by R. Hansel et al., Z. Naturforsch., 33b, p. 1020-1025 (1978).
However, the authors did not report anything about a pharmacological effectiveness or even of a therapeutic utility of the known compounds.
For the preparation of the known compounds, R. Hansel et al. loc. cit. suggest the isolation of 5,6-Z-piperolide from the species Piper sanctum indigenous to Mexico which can be converted by photon irradiation into the stereoisomeric 5,6-E-piperolide. By catalytic hydrogenation, 5,6-E-piperolide can be reacted to give 5,6-threo-tetrahydropiperolide (4-methoxy-5-(.alpha.-methoxy-.gamma.-phenylpropyl)-2(5H)-furanone). However, obtaining the starting material, i.e. the natural product 5,6-Z-piperolide, and its conversion into 5,6-E-piperolide is very expensive and, therefore, unsuitable for a commercial use.
Another known process for the preparation of the known compounds (cf. A. Pelter et al., Tetrahedron Lett., 1979, p. 1627-1630) starts from methyl tetronate, the preparation of which is known from European patent specification No. 10,288. Methyl tetronate is hereby mixed with lithium diisopropylamide with the formation of a carbanion and then reacted at -78.degree. C. with benzaldehyde or dihydrocinnamic aldehyde. Quite apart from the fact that the reaction conditions (-78.degree. C.!) are unsuitable for an economic preparation on a large scale, in the case of this process there always result mixtures of the threo and erythro diastereomers so that, for the separation of the threo compounds in pure form, laborious purification operations are necessary, insofar as the separation succeeds at all. Furthermore, the lithium organic compound employed is self-inflammatory and the hexamethylphosphoric acid triamide (HMPA) added as solubiliser is carcinogenic.
A series of variants of the process described by A. Pelter et al. are also known which, however, all possess the same principal disadvantages since they lead non-stereoselectively to one of the two diastereomeric pairs and, because of the necessary low temperatures, are very energy expensive.
Finally, a large series of compounds of the most differing chemical constitution with anticonvulsive and anti-epileptic effectiveness are also ready known (cf., for example, Ehrhart/Ruschig, Arzneimittel, Vol. 1, p. 177 et seq., pub. Verlag Chemie, Weinheim, 1972) to which belong, in particular, the active materials carbamazepine, diazepam, diphenylhydantoin, ethosuximide, phenobarbital and valproic acid. All these known anticonvulsives/anti-epileptics display chronic-toxic side effects to varying degrees, including exanthema, depressive states, paranoia, megaloblastic anaemia, damage of the blood-forming bone marrow, liver damage and others.
Therefore, there is a need for new pharmaceutical agents with anticonvulsive and anti-epileptic effectiveness because only thus is the physician able to select from a larger source of medicaments those agents the activity and side-effect spectra of which best satisfy the physical and psychic needs of the patients.